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261.
Iron-mediated inhibition of H+-ATPase in plasma membrane vesicles isolated from wheat roots 总被引:4,自引:0,他引:4
Yang YL Zhang F He WL Wang XM Zhang LX 《Cellular and molecular life sciences : CMLS》2003,60(6):1249-1257
The mechanisms of iron-mediated inhibition of the H(+)-ATPase activity of plasma membrane (PM) vesicles isolated from wheat roots were investigated. Both FeSO(4) and FeCl(3) significantly inhibited PM H(+)-ATPase activity, and the inhibition could be reversed by the addition of the metal ion chelator EDTA-Na(2) or a specific Fe(2+) chelator, indicating that the inhibitory effect was due to specific action of Fe(2+) or Fe(3+). Measurement of the extent of lipid peroxidation showed that oxidative damage on the PM caused by Fe(2+) or Fe(3+) seemed to be correlated with the inhibition of PM H(+)-ATPase activity. However, prevention of lipid peroxidation with butylated hydroxytoluene did not affect iron-mediated inhibition in the PM H(+)-ATPase, suggesting that the inhibition of the PM H(+)-ATPase was not a consequence of lipid peroxidation caused by iron. Investigation of the effects of various reactive oxygen species scavengers on the iron-mediated inhibition of H(+)-ATPase activity indicated that hydroxyl radicals (*OH) and hydrogen peroxide (H(2)O(2)) might be involved in the Fe(2+)-mediated decrease in PM H(+)-ATPase activity. Moreover, iron caused a decrease in plasma protein thiol (P-SH), and Fe(3+) brought a higher degree of oxidation in thiol groups than Fe(2+) at the same concentration. Modification of the thiol redox state in the PM suggested that reducing thiol groups were essential to maintain PM H(+)-ATPase activity. Incubation of the specific thiol modification reagent 5,5-dithio-bis(2-nitrobenzoic acid) with the rightside-out and inside-out PM revealed that thiol oxidation occurred at the apoplast side of the PM. Western blotting analysis revealed a decrease in H(+)-ATPase content caused by iron. Taken together, these results suggested that thiol oxidation might account for the inhibition of PM H(+)-ATPase caused by iron, and that *OH and H(2)O(2) were also involved in Fe(2+)-mediated inhibition. 相似文献
262.
Mutations in the gene encoding peroxisomal alpha-methylacyl-CoA racemase cause adult-onset sensory motor neuropathy 总被引:12,自引:0,他引:12
Ferdinandusse S Denis S Clayton PT Graham A Rees JE Allen JT McLean BN Brown AY Vreken P Waterham HR Wanders RJ 《Nature genetics》2000,24(2):188-191
Sensory motor neuropathy is associated with various inherited disorders including Charcot-Marie-Tooth disease, X-linked adrenoleukodystrophy/adrenomyeloneuropathy and Refsum disease. In the latter two, the neuropathy is thought to result from the accumulation of specific fatty acids. We describe here three patients with elevated plasma concentrations of pristanic acid (a branched-chain fatty acid) and C27-bile-acid intermediates. Two of the patients suffered from adult-onset sensory motor neuropathy. One patient also had pigmentary retinopathy, suggesting Refsum disease, whereas the other patient had upper motor neuron signs in the legs, suggesting adrenomyeloneuropathy. The third patient was a child without neuropathy. In all three patients we discovered a deficiency of alpha-methylacyl-CoA racemase (AMACR). This enzyme is responsible for the conversion of pristanoyl-CoA and C27-bile acyl-CoAs to their (S)-stereoisomers, which are the only stereoisomers that can be degraded via peroxisomal beta-oxidation. Sequence analysis of AMACR cDNA from the patients identified two different mutations that are likely to cause disease, based on analysis in Escherichia coli. Our findings have implications for the diagnosis of adult-onset neuropathies of unknown aetiology. 相似文献
263.
A mouse model for spinal muscular atrophy 总被引:1,自引:0,他引:1
The survival motor neuron gene is present in humans in a telomeric copy, SMN1, and several centromeric copies, SMN2. Homozygous mutation of SMN1 is associated with proximal spinal muscular atrophy (SMA), a severe motor neuron disease characterized by early childhood onset of progressive muscle weakness. To understand the functional role of SMN1 in SMA, we produced mouse lines deficient for mouse Smn and transgenic mouse lines that expressed human SMN2. Smn-/- mice died during the peri-implantation stage. In contrast, transgenic mice harbouring SMN2 in the Smn-/- background showed pathological changes in the spinal cord and skeletal muscles similar to those of SMA patients. The severity of the pathological changes in these mice correlated with the amount of SMN protein that contained the region encoded by exon 7. Our results demonstrate that SMN2 can partially compensate for lack of SMN1. The variable phenotypes of Smn-/-SMN2 mice reflect those seen in SMA patients, providing a mouse model for this disease. 相似文献
264.
Conditional inactivation of Fgf4 reveals complexity of signalling during limb bud development 总被引:12,自引:0,他引:12
Development of the vertebrate limb bud depends on reciprocal interactions between the zone of polarizing activity (ZPA) and the apical ectodermal ridge (AER). Sonic hedgehog (SHH) and fibroblast growth factors (FGFs) are key signalling molecules produced in the ZPA and AER, respectively. Experiments in chicks suggested that SHH expression in the ZPA is maintained by FGF4 expression in the AER, and vice versa, providing a molecular mechanism for coordinating the activities of these two signalling centres. This SHH/FGF4 feedback loop model is supported by genetic evidence showing that Fgf4 expression is not maintained in Shh-/- mouse limbs. We report here that Shh expression is maintained and limb formation is normal when Fgf4 is inactivated in mouse limbs, thus contradicting the model. We also found that maintenance of Fgf9 and Fgf17 expression is dependent on Shh, whereas Fgf8 expression is not. We discuss a model in which no individual Fgf expressed in the AER (AER-Fgf) is solely necessary to maintain Shh expression, but, instead, the combined activities of two or more AER-Fgfs function in a positive feedback loop with Shh to control limb development. 相似文献
265.
Msx2 deficiency in mice causes pleiotropic defects in bone growth and ectodermal organ formation 总被引:20,自引:0,他引:20
Satokata I Ma L Ohshima H Bei M Woo I Nishizawa K Maeda T Takano Y Uchiyama M Heaney S Peters H Tang Z Maxson R Maas R 《Nature genetics》2000,24(4):391-395
The composite structure of the mammalian skull, which forms predominantly via intramembranous ossification, requires precise pre- and post-natal growth regulation of individual calvarial elements. Disturbances of this process frequently cause severe clinical manifestations in humans. Enhanced DNA binding by a mutant MSX2 homeodomain results in a gain of function and produces craniosynostosis in humans. Here we show that Msx2-deficient mice have defects of skull ossification and persistent calvarial foramen. This phenotype results from defective proliferation of osteoprogenitors at the osteogenic front during calvarial morphogenesis, and closely resembles that associated with human MSX2 haploinsufficiency in parietal foramina (PFM). Msx2-/- mice also have defects in endochondral bone formation. In the axial and appendicular skeleton, post-natal deficits in Pth/Pthrp receptor (Pthr) signalling and in expression of marker genes for bone differentiation indicate that Msx2 is required for both chondrogenesis and osteogenesis. Consistent with phenotypes associated with PFM, Msx2-mutant mice also display defective tooth, hair follicle and mammary gland development, and seizures, the latter accompanied by abnormal development of the cerebellum. Most Msx2-mutant phenotypes, including calvarial defects, are enhanced by genetic combination with Msx1 loss of function, indicating that Msx gene dosage can modify expression of the PFM phenotype. Our results provide a developmental basis for PFM and demonstrate that Msx2 is essential at multiple sites during organogenesis. 相似文献
266.
SHATTERPROOF MADS-box genes control seed dispersal in Arabidopsis 总被引:34,自引:0,他引:34
The fruit, which mediates the maturation and dispersal of seeds, is a complex structure unique to flowering plants. Seed dispersal in plants such as Arabidopsis occurs by a process called fruit dehiscence, or pod shatter. Few studies have focused on identifying genes that regulate this process, in spite of the agronomic value of controlling seed dispersal in crop plants such as canola. Here we show that the closely related SHATTERPROOF (SHP1) and SHATTERPROOF2 (SHP2) MADS-box genes are required for fruit dehiscence in Arabidopsis. Moreover, SHP1 and SHP2 are functionally redundant, as neither single mutant displays a novel phenotype. Our studies of shp1 shp2 fruit, and of plants constitutively expressing SHP1 and SHP2, show that these two genes control dehiscence zone differentiation and promote the lignification of adjacent cells. Our results indicate that further analysis of the molecular events underlying fruit dehiscence may allow genetic manipulation of pod shatter in crop plants. 相似文献
267.
Cortex-restricted disruption of NMDAR1 impairs neuronal patterns in the barrel cortex 总被引:14,自引:0,他引:14
Iwasato T Datwani A Wolf AM Nishiyama H Taguchi Y Tonegawa S Knöpfel T Erzurumlu RS Itohara S 《Nature》2000,406(6797):726-731
In the rodent primary somatosensory cortex, the configuration of whiskers and sinus hairs on the snout and of receptor-dense zones on the paws is topographically represented as discrete modules of layer IV granule cells (barrels) and thalamocortical afferent terminals. The role of neural activity, particularly activity mediated by NMDARs (N-methyl-D-aspartate receptors), in patterning of the somatosensory cortex has been a subject of debate. We have generated mice in which deletion of the NMDAR1 (NR1) gene is restricted to excitatory cortical neurons, and here we show that sensory periphery-related patterns develop normally in the brainstem and thalamic somatosensory relay stations of these mice. In the somatosensory cortex, thalamocortical afferents corresponding to large whiskers form patterns and display critical period plasticity, but their patterning is not as distinct as that seen in the cortex of normal mice. Other thalamocortical patterns corresponding to sinus hairs and digits are mostly absent. The cellular aggregates known as barrels and barrel boundaries do not develop even at sites where thalamocortical afferents cluster. Our findings indicate that cortical NMDARs are essential for the aggregation of layer IV cells into barrels and for development of the full complement of thalamocortical patterns. 相似文献
268.
Nicastrin modulates presenilin-mediated notch/glp-1 signal transduction and betaAPP processing 总被引:26,自引:0,他引:26
Yu G Nishimura M Arawaka S Levitan D Zhang L Tandon A Song YQ Rogaeva E Chen F Kawarai T Supala A Levesque L Yu H Yang DS Holmes E Milman P Liang Y Zhang DM Xu DH Sato C Rogaev E Smith M Janus C Zhang Y Aebersold R Farrer LS Sorbi S Bruni A Fraser P St George-Hyslop P 《Nature》2000,407(6800):48-54
Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes with presenilin 1 and presenilin 2. Suppression of nicastrin expression in Caenorhabditis elegans embryos induces a subset of notch/glp-1 phenotypes similar to those induced by simultaneous null mutations in both presenilin homologues of C. elegans (sel-12 and hop-1). Nicastrin also binds carboxy-terminal derivatives of beta-amyloid precursor protein (betaAPP), and modulates the production of the amyloid beta-peptide (A beta) from these derivatives. Missense mutations in a conserved hydrophilic domain of nicastrin increase A beta42 and A beta40 peptide secretion. Deletions in this domain inhibit A beta production. Nicastrin and presenilins are therefore likely to be functional components of a multimeric complex necessary for the intramembranous proteolysis of proteins such as Notch/GLP-1 and betaAPP. 相似文献
269.
LDL-receptor-related proteins in Wnt signal transduction 总被引:58,自引:0,他引:58
Tamai K Semenov M Kato Y Spokony R Liu C Katsuyama Y Hess F Saint-Jeannet JP He X 《Nature》2000,407(6803):530-535
The Wnt family of secreted signalling molecules are essential in embryo development and tumour formation. The Frizzled (Fz) family of serpentine receptors function as Wnt receptors, but how Fz proteins transduce signalling is not understood. In Drosophila, arrow phenocopies the wingless (DWnt-1) phenotype, and encodes a transmembrane protein that is homologous to two members of the mammalian low-density lipoprotein receptor (LDLR)-related protein (LRP) family, LRP5 and LRP6 (refs 12-15). Here we report that LRP6 functions as a co-receptor for Wnt signal transduction. In Xenopus embryos, LRP6 activated Wnt-Fz signalling, and induced Wnt responsive genes, dorsal axis duplication and neural crest formation. An LRP6 mutant lacking the carboxyl intracellular domain blocked signalling by Wnt or Wnt-Fz, but not by Dishevelled or beta-catenin, and inhibited neural crest development. The extracellular domain of LRP6 bound Wnt-1 and associated with Fz in a Wnt-dependent manner. Our results indicate that LRP6 may be a component of the Wnt receptor complex. 相似文献
270.
A beta peptide immunization reduces behavioural impairment and plaques in a model of Alzheimer's disease 总被引:50,自引:0,他引:50
Janus C Pearson J McLaurin J Mathews PM Jiang Y Schmidt SD Chishti MA Horne P Heslin D French J Mount HT Nixon RA Mercken M Bergeron C Fraser PE St George-Hyslop P Westaway D 《Nature》2000,408(6815):979-982
Much evidence indicates that abnormal processing and extracellular deposition of amyloid-beta peptide (A beta), a proteolytic derivative of the beta-amyloid precursor protein (betaAPP), is central to the pathogenesis of Alzheimer's disease (reviewed in ref. 1). In the PDAPP transgenic mouse model of Alzheimer's disease, immunization with A beta causes a marked reduction in burden of the brain amyloid. Evidence that A beta immunization also reduces cognitive dysfunction in murine models of Alzheimer's disease would support the hypothesis that abnormal A beta processing is essential to the pathogenesis of Alzheimer's disease, and would encourage the development of other strategies directed at the 'amyloid cascade'. Here we show that A beta immunization reduces both deposition of cerebral fibrillar A beta and cognitive dysfunction in the TgCRND8 murine model of Alzheimer's disease without, however, altering total levels of A beta in the brain. This implies that either a approximately 50% reduction in dense-cored A beta plaques is sufficient to affect cognition, or that vaccination may modulate the activity/abundance of a small subpopulation of especially toxic A beta species. 相似文献